Method and apparatus for diagnostic and therapeutic agent delivery

ABSTRACT

Method and apparatus for diagnostic and therapeutic agent delivery is provided by the present invention. In one embodiment a method for injecting an agent into the body of a patient is provided. This method includes: covering an injection structure having a piercing tip with a coating that contains a first agent; urging the piercing tip of the injection structure into a first target located in the body of the patient; and, maintaining the injection structure in the first target location for a predetermined amount of time. In so doing the agent may be conveniently and accurately delivered to the target site. In another embodiment of the present invention a drug delivery device is provided. This drug delivery device includes a catheter having a proximate end and a distal end and an injection structure coupled to the distal end of the catheter. In this embodiment the catheter is covered with a coating that contains an agent. This coating is adapted to release the agent into the body of a patient after the coating enters the body of the patient; again to conveniently and accurately deliver the agent to the target site.

FIELD OF THE INVENTION

The present invention regards the delivery of therapeutic and diagnosticagents to a target site of a patient. More particularly the presentinvention regards method and apparatus for minimizing the amount ofbackflow or seepage of therapeutic and diagnostic agents from a targetsite after the agent has been delivered to the target site.

BACKGROUND OF THE INVENTION

Accurate and reliable delivery of therapeutic and diagnostic agents isrequired for the successful execution of numerous medical procedures. Inthe past, however, the accurate and reliable delivery of these agentsduring a medical procedure was not always plausible. For example, when asyringe is utilized to deliver an agent to a target site within the bodysome, if not all, of the injected agent may passively drain from thetarget site after the needle of the syringe is removed from the targetsite. This undesirable drainage is accentuated when the target site isan active muscle such as the heart. Here, the agent would not onlypassively drain from the open channel created by the removal of theneedle, it would also be actively forced from the open channel duringeach muscular contraction.

The drainage of these agents after their injection into the body isproblematic for several reasons. First, when a portion of the agentdrains away from the injection site it is no longer available to treatthe target site and is, consequently, wasted. Moreover, when the agentdrains from the target site, but still remains within the body, theagent can interact with and effect other sites within the body of thepatient. This unwanted contact and interaction can lead to complicationsand unpredictable results. In addition, the untimely drainage of theagent from the targeted site may render the agent ineffective becausethe agent did not remain in contact with the targeted site for therequisite interaction time. Consequently, the agent would need to bereintroduced to the target site through a second procedure. In sum, theuncontrolled drainage of an agent from a targeted site of the body is anobjectionable occurrence.

Some conventional processes seek to address this problem. In one knownprocess an erodible polymer is utilized to deliver the drug to atargeted site over a long period of time. In this known process theerodible polymers are blended with a drug and then deposited at thetargeted site requiring their use. Over time, the polymer will slowlyerode and, concomitantly, delivery the drug to its surrounding area.However, when the targeted site is not readily accessible in the body,substantial operative procedures may be required to properly positionthe polymer within the body. In addition, when the drug needs to bedelivered over a short period of time, the polymer can erode tooquickly, allowing the premature drainage of drug. Likewise, if the drugis to be delivered for an extended period of time, the polymer may noterode quickly enough and the drug will be delivered over an unacceptablylong time frame.

Accordingly, in view of the potential drawbacks of conventional drugdelivery techniques, there exists a need for a method and device thatprovide for the controlled, localized delivery of agents to targetlocations in the body which avoid the unwanted shortcomings encounteredin the past.

SUMMARY OF THE INVENTION

Method and apparatus for diagnostic and therapeutic agent delivery isprovided by the present invention. In one embodiment a method forinjecting an agent into the body of a patient is provided. This methodincludes: covering an injection structure having a piercing tip with acoating that contains a first agent; urging the piercing tip of theinjection structure into a first targeted site located in the body ofthe patient; and, maintaining the injection structure in the firsttargeted site location for a predetermined amount of time. In so doingthe agent may be conveniently and accurately delivered to the targetsite.

In another embodiment of the present invention a drug delivery device isprovided. This drug delivery device includes a catheter having aproximate end and a distal end and an injection structure coupled to thedistal end of the catheter. In this embodiment the injection structureis covered with a coating that contains an agent. This coating isadapted to release the agent into the body of a patient after thecoating enters the body of the patient; again to conveniently andaccurately deliver the agent to the target site.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a side view of a delivery device in accordance with a firstembodiment of the present invention.

FIG. 2 is an enlarged view of the distal end of the delivery device ofFIG. 1 positioned near a target site.

FIG. 3 is a side view of the delivery device of FIG. 1 after it hasentered the target site.

FIG. 4 is a side view of the delivery device of FIG. 1 positioned withinthe target site after the plunger of the delivery device has beenpartially depressed.

FIG. 5 is a side view of a catheter in accordance with a secondembodiment of the present invention.

FIG. 6 is an end view of the catheter taken along line 6—6 of FIG. 5.

FIG. 7 is an enlarged view of the distal end of the catheter from FIG. 5with the injection structure shown protruding from the distal end of thecatheter.

FIG. 8 is a side view of a catheter in accordance with a thirdembodiment of the present invention.

FIG. 9 is an enlarged view of the distal end of a catheter in accordancewith a fourth embodiment of the present invention.

FIG. 10 is a side cross-sectional view of an injection catheter inaccordance with a fifth embodiment of the present invention.

FIG. 11 is an enlarged cross-sectional view of the connection pointbetween the catheter and the activator gun of FIG. 10.

FIG. 12 is an enlarged cross-sectional view of the catheter from FIG.10.

DETAILED DESCRIPTION

FIG. 1 is a side view of a delivery device 10 in accordance with a firstembodiment of the present invention. The delivery device 10 in thisfirst embodiment has an injection structure 15 rigidly andperpendicularly coupled to a storage reservoir 11. The storage reservoir11 may be tube shaped and may have a circular cross-section. Slidablymounted within the storage reservoir 11 is a rigid disc 19 which definesa chamber 7 in the distal end of the storage reservoir 11. A rigidconnector 12 is perpendicularly connected to the disc 19 and to a handle13 located outside the storage reservoir 11. This connector 12 connectsthe disc 19 with the handle 13 such that when the handle 13 is moved thedisc 19 is concomitantly slid within the storage reservoir 11, reducingthe volume of the chamber 7 and, thereby, forcing any contents of thechamber 7 through the lumen 18 of the injection structure 15 and out theorifice 17 located at the distal end of the injection structure 15. Thedistal end of the injection structure 15, which may have a circularcross-sectional profile in this first embodiment, also has a piercingtip 8 at its distal end. This piercing tip 8 may have a sharp pointdesigned to puncture into soft tissue, hard tissue or bone.

The storage reservoir 11, handle 13, connector 12, and disc 19 may bemade from plastic, metal, a combination thereof or some other suitablematerial. Likewise, the injection structure 15 may also be made fromplastic, metal, a combination thereof or some other suitable material.For example, in this first embodiment, in order to maintain a sharp andresilient piercing tip 8, the injection structure 15 may be made from arigid plastic while the piercing tip 8 may be made from a surgical metalalloy.

Also evident in FIG. 1 is a coating 16, which, as can be seen, may covera large portion of the injection structure 15. In this first embodimenta first agent 9 is contained by the coating, through absorption by thecoating. The first agent may also be contained by the coating 16 throughadsorption or any other means. A second agent 14 may be located withinthe chamber 7. The first agent 9 may be a therapeutic, a diagnostic orany other suitable agent and the second agent 14 may be an uptake agent,an anti-inflammatory agent, an anesthetic or, likewise, any othersuitable agent. These first and second agents may work alone to produceindependent results; they may also work together to produce cumulativelybeneficial results. The injection structure 15 of the delivery device 10may be used to deliver the first agent 9, which is located in thecoating 16, to a target site (not shown) of a patient.

In use, the delivery device 10 may be first positioned near the targetsite by known percutaneous or endoluminal techniques which manipulatethe device through blood vessels or other lumens and cavities within thebody. Then, after being properly positioned near the target site, theinjection structure may be urged into the target site of the patient,thereby creating an injection channel defined by the outer surface ofthe coating 16. The injection structure 15 may then remain within thetarget site until the proper dosage of the first agent 9 has beendelivered to the target site from the coating 16. The length of timerequired to deliver the requisite dosage will depend upon many factorsincluding the agent being delivered and the composition of the targetsite; it can be a few seconds to several minutes or 40 more. During thistime, as required by the specific circumstances of the procedure, asecond agent 14, resident within the chamber 7, may or may not beintroduced into the target site. This second agent 14, which, as notedabove, may be an anti-inflammatory, an uptake agent, or any other typeof agent, may be introduced into the target site by depressing thehandle 13 and ultimately urging the second agent 14 from the orifice 17.Then, after the requisite agent or agents have been deployed and thenecessary time has passed, allowing the agent or agents to interact witheach other and the target site, the injection structure 15 may beremoved from the target site.

Organs and tissues that may be treated by the method of the presentinvention include any mammalian tissue or organ, whether injected invivo or ex vivo. Specific, non-limiting examples include heart, lung,brain, liver, skeletal muscle, smooth muscle, kidney, bladder,intestines, stomach, pancreas, ovary, prostate, eye, tumors, cartilage,and bone.

The therapeutic agents deployed may be used in any application includingthe treating, preventing or otherwise affecting the course of a disease,tissue or organ dysfunction. For example, the methods of the inventioncan be used, as desired, to induce or inhibit angiogenesis to prevent ortreat restenosis, to treat a cardiomyopathy or other dysfunction of theheart, for treating Parkinson's disease, a stroke or other dysfunctionof the brain, for treating cystic fibrosis or other dysfunction of thelung, for treating or inhibiting malignant cell proliferation, fortreating any malignancy, and for inducing nerve, blood vessel or tissueregeneration in a particular tissue or organ.

FIG. 2 is an enlarged side view of the distal end 22 of the injectionstructure 15 from FIG. 1. In FIG. 2 the target site 21 to be pierced isclearly shown. This target site 21 may be an organ or a hard or softtissue location within the patient, including the heart, bladder, liver,prostate, as well as a growth or tumor situated within the body of apatient. Also evident in FIG. 2 is the injection structure 15, the lumen18 within the injection structure 15, the orifice 17 near the piercingtip 8 of the injection structure 15, and the coating 16 which containsthe first agent 9. The arrow 20 of FIG. 2 indicates a preferreddirection of movement of the injection structure 15 towards the targetsite 21.

FIG. 3 is a side view of the delivery device 10 from FIG. 1 after it hasentered the target site 21. As can be seen the injection structure 15has created an injection channel 33 defined by the outer surface of thecoating 16. As can also be seen the coating 16 may become pushed awayfrom the point of the piercing tip 8 and has also mounded up near thepoint of entry 32 of the injection structure 15 in the target site 21,depending upon the coating materials used. The coating 16 has beendisplaced in this manner due to the opposing frictional resistance ofthe target site 21 against the injection structure 15 during theinjection of the injection structure 15 into the target site 21. Oncethe injection structure 15 and the coating 16 have entered the targetsite 21 the first agent 9, resident in the coating 16, may diffuse intothe surrounding tissue. The diffusion of the first agent 9 into thesurrounding target site 21 is depicted with arrows 30 in FIG. 3.

The coating 16 and the first agent 9 described above may be applied tothe injection structure 15 at various times and in various ways. Forexample, they may be applied prior to the medical procedure and duringthe manufacturing process. They may also be spread onto the injectionstructure 15 contemporaneous with the medical procedure being performed,by dipping the injection structure into a container containing thecoating. When the coating is placed by the manufacturer onto the device,the injection structure 15 may be covered with a sheath or some othermaterial to prevent the premature removal of the coating 16 or the firstagent 9 from the injection structure 15. Alternatively, the coating andthe agent may be applied to the rigid structure at different times. Forexample, the coating may be applied by the manufacturer during themanufacture of the device while the agent may be applied by the operatorcontemporaneous with the procedure.

FIG. 4 is a side view of the injection device 10 wherein the secondagent 14, resident in the chamber 7, is being forced through the orifice17 into the target site 21. As noted above, this second agent 14 may beutilized to increase the cellular uptake of the first agent 9 into thetarget site 21 and, accordingly, may also be used to reduce the amountof time required to leave the injection structure 15 in the injectionchannel 33. FIG. 4 illustrates the second agent exiting the orifice 17with arrows 40 and also indicates the directional movement of the disc19, with arrows 42, as it is used to urge the second agent 14 out theorifice 17. In other embodiments, the orifice 17 may be located inalternative positions such as the side of the injection structure;moreover, several orifices rather than only one may be located atvarious locations in the injection structure.

The first agent 9 resident within the coating to be delivered to thetarget site may be, among other things, a therapeutic, a tracermaterial, and a diagnostic agent. The therapeutic may includetherapeutic agents such as pharmaceutically active compounds, proteins,cells, oligonucleotides, ribozymes, anti-sense oligonucleotides, DNAcompacting agents, gene/vector systems (i.e., any vehicle that allowsfor the uptake and expression of nucleic acids), nucleic acids(including, for example, recombinant nucleic acids; naked DNA, cDNA,RNA; genomic DNA, cDNA or RNA in a non-infectious vector or in a viralvector and which further may have attached peptide targeting sequences;antisense nucleic acid (RNA or DNA); DNA chimeras which include genesequences and encoding for ferry proteins such as membrane translocatingsequences (“MTS”) and herpes simplex virus-1 (“VP22”)); viral liposomes;cationic and anionic polymers; and, neutral polymers that are selectedfrom a number of types depending on the desired application.

Non-limiting examples of virus vectors or vectors derived from viralsources include adenoviral vectors, herpes simplex vectors, papillomavectors, adeno-associated vectors, retroviral vectors, and the like.

Non-limiting examples of biologically active solutes include:anti-thrombogenic agents such as heparin, heparin derivatives,urokinase, and PPACK (dextrophenylalanine proline argininechloromethylketone); antioxidants such as probucol and retinoic acid;angiogenic and anti-angiogenic agents and factors; agents blockingsmooth muscle cell proliferation such as rapamycin, angiopeptin, andmonoclonal antibodies capable of blocking smooth muscle cellproliferation; anti-inflammatory agents such as dexamethasone,prednisolone, corticosterone, budesonide, estrogen, sulfasalazine,acetyl salicylic acid, and mesalamine; calcium entry blockers such asverapamil, diltiazem and nifedipine;antineoplastic/antiproliferative/anti-mitotic agents such as paclitaxel,5-fluorouracil, methotrexate, doxorubicin, daunorubicin, cyclosporine,cisplatin, vinblastine, vincristine, epothilones, endostatin,angiostatin and thymidine kinase inhibitors; antimicrobials such as totriclosan, cephalosporins, aminoglycosides, and nitorfurantoin;anesthetic agents such as lidocaine, bupivacaine, and ropivacaine;nitric oxide (NO) donors such as lisidomine, molsidomine, L-arginine,NO-protein adducts, NO-carbohydrate adducts, polymeric or oligomeric NOadducts; anti-coagulants such as D-Phe-Pro-Arg chloromethyl ketone, anRGD peptide-containing compound, heparin, antithrombin compounds,platelet receptor antagonists, anti-thrombin antibodies, anti-plateletreceptor antibodies, enoxaparin, hirudin, Warafin sodium, Dicumarol,aspirin, prostaglandin inhibitors, platelet inhibitors and tickantiplatelet factors; vascular cell growth promotors such as growthfactors, growth factor receptor antagonists, transcriptional activators,and translational promotors; vascular cell growth inhibitors such asgrowth factor inhibitors, growth factor receptor antagonists,transcriptional repressors, translational repressors, replicationinhibitors, inhibitory antibodies, antibodies directed against growthfactors, bifunctional molecules consisting of a growth factor and acytotoxin, bifunctional molecules consisting of an antibody and acytotoxin; cholesterol-lowering agents; vasodilating agents; agentswhich interfere with endogeneus vascoactive mechanisms; survival geneswhich protect against cell death, such as anti-apoptotic Bcl-2 familyfactors and Akt kinase; and combinations thereof. Cells can be of humanorigin (autologous or allogenic) or from an animal source (xenogeneic),genetically engineered if desired to deliver proteins of interest at theinjection site. The delivery mediated is formulated as needed tomaintain cell function and viability, and modifications are routinelymade by one skilled in the art.

Polynucleotide sequences useful as an agent in practice of the inventioninclude DNA or RNA sequences having a therapeutic effect after beingtaken up by a cell. Examples of therapeutic polynucleotides includeanti-sense DNA and RNA; DNA coding for an anti-sense RNA; or DNA codingfor tRNA or rRNA to replace defective or deficient endogenous molecules.The polynucleotides of the invention can also code for therapeuticproteins or polypeptides. A polypeptide is understood to be anytranslation product of a polynucleotide regardless of size, and whetherglycosylated or not. Therapeutic proteins and polypeptides include as aprimary example, those proteins or polypeptides that can compensate fordefective or deficient species in an animal, or those that act throughtoxic effects to limit or remove harmnful cells from the body. Inaddition, the polypeptides or proteins that can be utilized, or whoseDNA can be incorporated, include without limitation, angiogenic factorsand other molecules competent to induce angiogenesis, including acidicand basic fibroblast growth factors, vascular endothelial growth factor,hif-1, epidermal growth factor, transforming growth factor α and β,platelet-derived endothelial growth factor, platelet-derived growthfactor, tumor necrosis factor α, hepatocyte growth factor and insulinlike growth factor; growth factors; cell cycle inhibitors including CDKinhibitors; anti-restenosis agents, including p15, p16, p18, p19, p21,p27, p53, p57, Rb, nFkB and E2F decoys, thymidine kinase (“TK”) andcombinations thereof and other agents useful for interfering with cellproliferation, including agents for treating malignancies; andcombinations thereof.

Still other useful factors, which can be provided as polypeptides or asDNA encoding these polypeptides, include monocyte chemoattractantprotein (“MCP-1”), and the family of bone morphogenic proteins(“BMP's”). The known proteins include BMP-2, BMP-3, BMP-4, BMP-5, BMP-6(Vgr-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13,BMP-14, BMP-15, and BMP-16. Currently preferred BMP's are any of BMP-2,BMP-3, BMP-4, BMP-5, BMP-6 and BMP-7. These dimeric proteins can beprovided as homodimers, heterodimers, or combinations thereof, alone ortogether with other molecules. Alternatively or, in addition, moleculescapable of inducing an upstream or downstream effect of a BMP can beprovided. Such molecules include any of the “hedgehog” proteins, or theDNA's encoding them.

Examples of the diagnostic agents useful for the practice of the presentinvention include: Corticotropin, Cosyntropin,Benzylpenicilloyl-Polylysine, Candida Albicans, Histoplasmin, Sincalide,Lactose, Indigotindisulfonate, Mannitol, Edrophonium, Neostigmine,Arginine, Ditrizoate Meglumine, Diatrizoate Sodium, Gadopentetate,lodixanol, lohexol, Tuberculin, Fluorescein Sodium, Fluorexon,Histamine, Isosulfan Blue, Methacholine, Rose Bengal, and FluoresceinSodium.

The coating discussed herein may be one of several commerciallyavailable materials. Further to the above, it may be a swellable porouspolymer used to absorb a volume of concentrated agent that, when placedwithin the target site, facilitates the diffusion of the first agentinto the target site according to a known concentration and diffusiongradient. Alternatively, the coating may be a charged polymer which mayadsorb high concentrations of oppositely charged agent, and, then, mayrelease the agent upon contact of the polymer with the target site.Moreover, the polymer may also have properties which allow it to shrinkor change ionic character, thereby facilitating the release of the agentfrom the coating in response to an environmental stimuli such as pH,ionic strength of the target site, pressure, and temperature. Forexample, if the therapeutic agent is dissolved in the polymer at acertain pH, the swollen polymer will then shrink when placed into thetissue at a different physiological pH. Alternatively, the release ofthe first agent could be triggered by the second agent 14, locatedwithin the chamber 7. In this case, the uptake agent 14 or triggeringsolution would be a buffer or salt solution which would be deliveredthrough the lumen while the injection structure 15 was resident withinthe target site 21. Then, after coming in contact both with the targetsite 21 and the polymer containing the agent, the uptake agent 14 wouldfacilitate the diffusion of the agent into the target site 21. Moreover,as discussed below, rather than remaining on the injection structure,the polymer may also be released from the injection structure and remainwithin the body after the injection structure is removed.

Specific suitable biocompatible polymers for use in the presentinvention include, but are not limited to, polycarboxylic acids,cellulosic polymers, including cellulose acetate and cellulose nitrate,gelatin, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone,hydrogels, polyanhydrides including maleic anhydride polymers,polyamides, polyvinyl alcohols, copolymers of vinyl monomers such asEVA, polyvinyl ethers, polyvinyl aromatics, polyethylene oxides,glycosaminoglycans, polysaccharides, ethylene vinylacetate, polyestersincluding polyethylene terephthalate, polyacrylamides, polyethers,polyether sulfone, polycarbonate, polyalkylenes including polypropylene,polyethylene and high molecular weight polyethylene, halogenatedpolyalkylenes including polytetrafluoroethylene, polyurethanes,polyorthoesters, proteins, polypeptides, silicones, siloxane polymers,polylactic acid, polyglycolic acid, polycaprolactone,polyhydroxybutyrate valerate and blends and copolymers thereof as wellas other biodegradable, bioabsorbable and biostable polymers andcopolymers.

Like the various coatings and first agents listed above various secondagents may also be utilized in the present invention. For example,certain detergents, polymers (polyvinyl pyrrolidone SP 1017 (SupratekPharma), protamine sulfate, and polysine), and drugs (anti-inflammatory,anti-apoptotic, angiogenic and vessel stabilizing) may be injected intothe target site to improve the effectiveness of the present invention.

A second embodiment of the present invention is illustrated in FIG. 5.As can be seen, the catheter 50 in FIG. 5 contains: a push rod 51centrally located within the catheter 50; a disk 52 slidably movablewithin the catheter 50 and rigidly coupled to the push rod 51; a tubularinjection structure 53 also located within the catheter 50 and rigidlycoupled to the disk 52; supports 56, supporting the dispensing chamber54 in the center of the circular catheter 50; and, a piercing tip 55located at the distal end of the injection structure 53. Like thedelivery device 10 above, catheter 50 may also be used to deliver agentsto a target site within the body.

FIG. 6 is a view taken from line 6—6 of FIG. 5. As can be seen in FIG.6, the catheter 50 in this embodiment has a substantially circularcross-section, supports 56 support the dispensing chamber 54 in thecenter of the catheter 50, and dispensing chamber 54, has a circularcross-section and an opening 57 at its distal end. This opening 57,allows the piercing tip 55 of the injection structure 53 (not shown inthis figure) to exit the dispensing chamber 54 with a coating of polymersurrounding it. In other words, the exit orifice 57, of the dispensingchamber 54 is sized to act as a squeegee which passes a predeterminedamount of polymer stored within the dispensing chamber 54 onto theinjection structure 53 as the injection structure 53 is pushed throughand emerges from the dispensing chamber 54. Alternatively, thedispensing chamber could contain the first agent which may be absorbedonto the polymer resident on the injection structure when the injectionstructure was retracted into the dispensing chamber. In this alternativeembodiment, the dispensing chamber would contain the first agent, butnot necessarily the polymer.

In use, an operator would position the distal end of the catheter 50near the target site (not shown). Next, the injection structure 53 wouldbe pushed through the dispensing chamber 54 containing a polymer and afirst agent in order to first coat the injection structure 53 and thento pierce into the targeted site. The injection structure would continueto be pushed through the dispensing chamber 54 and into the target siteuntil the requisite amount of the injection structure 53 had entered thetarget site. Then, after keeping the injection structure in the targetedsite of the body until the first agent had diffused into the targetedsite of the body, the operator would extract the injection structure 53from the target site and the injection channel by pulling on the handle58 or, alternatively, by pulling on the proximate end of the catheter.

This coating and injection procedure may be repeated for the sameinjection channel by pushing the handle 58 and again driving theinjection structure 53 through the dispensing chamber 54 and into thetarget site. Alternatively, the procedure may be repeated for adifferent targeted site by repositioning the distal end of the catheter50 and then by driving the injection structure 53 through the dispensingchamber 54 into the new target site. In either case, the procedure maybe repeated until the requisite amount of first agent has beenadministered or until the contents of the dispensing chamber have beendepleted. When additional agent needs to be delivered to the targetsite, but the contents of the dispensing chamber 54 have been depleted,the catheter 50 may be disposed of and a new one may be used.Alternatively, a new dispensing chamber 54 may be inserted into thedistal end of the catheter 50 or the existing dispensing chamber may berefilled.

FIG. 7 is an enlarged view of the distal end of the catheter 50 fromFIG. 5. In FIG. 7, the disk 52 has been slid closer to the distal end ofthe catheter 50 as indicated by arrows 71 and, the injection structure53, which has been coated with the polymer 70, now protrudes from theend of the catheter 50.

In use and as described above, the injection structure 53 may be slidthrough the dispensing chamber 53 and directly into the target site.Alternatively, the catheter may be positioned away from the target sitewhen the injection structure 53 is slid through the dispensing chamber54 to load the polymer 70. Then, as required, the injection structure,now protruding from the distal end of the catheter 50, may be inserteddirectly into the target site. An advantage of loading the polymer 70onto the injection structure 53 prior to positioning the catheter nearthe target site is that the injection structure 53, protruding from thedistal end of the catheter 50, may be used to assist in the positioningof the catheter 50 near the target site.

FIG. 8 is a side view of a third embodiment of the present invention. InFIG. 8, a handle 89 is rigidly connected to a circular sliding disc 891which is in contact with a storage reservoir 83 which may contain anuptake agent 84. The storage reservoir 83 is connected to and is influid communication with a tube 82 located within the catheter 87. Thetube 82 connects the storage reservoir 83 with the lumen 81 of thesyringe 88. The tube 82, like the catheter 87 and the storage reservoir83, may be circular and may be made from a surgical grade polymer.

The needle 88 of FIG. 8 is rigidly coupled to the distal end of the tube82. The needle 88 contains an orifice 85 which is in communication withthe lumen 81 and is located on the side of the needle. The needle 88also contains a piercing tip 86 at its distal end. This piercing tip maybe made from various rigid and hard materials such as iron, steel, orother surgical grade alloys and should be configured to permit it topuncture into targeted tissue sites located within the body of thepatient.

As is evident in FIG. 8, the needle 88 has been pretreated with apolymer 80 and is consequently ready for use. As described above, thepiercing tip 86 of the needle 88 will first be positioned adjacent to atarget site. Next, the operator will push the needle 88 into the targetsite and support the needle 88 within the target site for apredetermined amount of time. If required, after the needle 88 hasentered the target site, thereby creating the injection channel withinthe target site, the uptake agent 84, resident within the storagereservoir 83, may be squeezed from the storage reservoir 83, urgedthrough the tube 82, into the lumen 81, and out the orifice 85. As notedabove, this uptake agent may be used to reduce the amount of timerequired to deliver the agent to the target site or for other purposessuch as inflamation reduction and anesthetic delivery. After the agentin the coating has been properly delivered the needle may be removedfrom the target site.

FIG. 9 is an enlarged view of the distal end of a catheter 96 inaccordance with a fourth embodiment of the present invention. Arrows 95in this embodiment illustrate the direction of movement of the disk 94within the catheter 96. As is evident, a flexible tube 90 may be coupledto one side of the disk 94 and a needle 91 may be coupled to the otherside of the disc 94. The flexible tube 90 and the needle 91 may be influid communication with each other through the disk 94. The flexibletube 90 connects the disk 94 with a storage reservoir (not shown). Thisflexible tube 90 is sized to connect the disc 94 with the storagereservoir when the disc 94 has been slid to its furthest point from thestorage reservoir. Consequently, as is evident in FIG. 9, the flexibletube 90 will sag within the catheter 96 when the disc 94 is notpositioned at its furthest point from the storage reservoir.

The distal end of the catheter in FIG. 9 also contains an orifice 92located near the distal end of the needle 91. This orifice 92 may be influid communication with the lumen 93 located within the needle 91 whichmay be in turn in fluid communication with the flexible tube 90.

In use, when required during the procedure, the operator can push thehandle (not shown) connected to the pushrod 99 to slide the disc 94towards the distal end of the catheter 96. As the disc is slid, theneedle 91, coupled to the disc 94, will be pushed through the dispensingchamber 98 out the distal end of the catheter 96 and into the targetsite 901 of the patient. The needle will remain there for apredetermined amount of time dependent upon the agent being deliveredfrom the polymer and the properties of the target site. If required, andas discussed above, an uptake agent may be delivered through theflexible tube 90 and out the orifice 92 of needle 91 into the targetedsite. Then, upon the completion of the procedure, the needle 91 would beremoved from the targeted site.

FIG. 10 is a side view of a fifth and preferred embodiment of thepresent invention, which uses a PMR catheter assembly 110 including adosage actuator gun 112 and catheter 14. In this embodiment, gun 112includes a body 116. Slidably disposed within body 116 and schematicallyshown in FIG. 10 is a syringe 118, slider body 120 and plunger 124.Syringe 118, slider body 120 and plunger 124 are slidable proximally anddistally as shown by the arrows adjacent these respective elements.Trigger 122 is pivotally connected about pin 123 to body 116. It can beappreciated that those skilled in the art of mechanical design couldreadily fashion a gun 112 based on the schematic description herein.

Catheter 114 includes an inner tubular shaft 126. Inner tubular shaft126 includes a sharpened distal end 127. Like syringe 118, slider 120and plunger 124, inner shaft 126 can be moved proximally or distally asshown by the arrows. More particularly, inner shaft 126 can be movedfrom a proximal position A wherein tip 127 is disposed within an outershaft 129 of catheter 114 to a second position B, wherein tip 127 isdisposed distally of outer shaft 129.

Syringe 118 includes an inner chamber 130 for containing a dosage of adrug or other fluid. Disposed at the distal end of plunger 124 is aplunger seal 132. Syringe 118 including plunger seal 132 preferably arepackaged to contain a second agent prior to placement in gun 112.Syringe 118 includes a Luer fitting 128 or similar attachment device tofluidly connect inner shaft 126 to syringe 118. The proximal ends ofplunger 124 includes a handle 134. Handle 134 can be used to rotateplunger 124 about its longitudinal axis within housing 116. Plunger 124includes a plurality of teeth 136 extending therefrom. Syringe 118 alsoincludes a cradle 138 in which is disposed a one-way plunger lock 140which is biased toward plunger 124 by spring 142. Lock 140 includes oneor more teeth having a slope which allows teeth 136 of plunger 124 to beadvanced distally thereover, but engages with teeth 136 to preventplunger 124 from being withdrawn proximally. Plunger 124 can, however,be withdrawn proximally if it is rotated about its longitudinal axis byusing handle 134 such that teeth 136 are disposed away from lock 140,for example, pointed upward rather than downward as shown in FIG. 10.

Slider 120 includes a syringe restraint member 144 which includes asurface engageable with cradle 138 of syringe 118. A plunger advancingmember 146 is pivotally attached to slider 120 by pin 148. A spring 150biases advancing member 146 toward a vertical position as shown in FIG.10. As slider 120 moves proximally relative to plunger 124, advancingmember 146 pivots downwardly as shown by the arrow allowing slider 120to move proximally relative to plunger 124. Advancing member 146,however, will pivot back to the vertical position after passing over atooth 136 and be braced in the vertical position by slider 120 to engagethe vertical proximal side of one of the teeth 136. Slider 120 includesa slot 152. A pin 156 extends through an end of trigger 122 and isslidable within slot 152. A spring 158 biases trigger 122 into theposition shown. Trigger 122 is, however, pivotable in the directionshown by the arrow about pin 123 between the position shown and anadjustment screw 160. Adjustment screw 160 has a distal end 161 which isengageable with trigger 122 to limit the pivoting of trigger 122 in aclockwise direction about pin 123.

Catheter 114 includes a preferably radiopaque, atraumatic hood 163 atits distal end and a manifold 164 at its proximal end. Manifold 164includes a port 166 for infusion or withdrawal of fluids from catheter114 through a lumen defined between inner shaft 126 and outer shaft 129.Manifold 164 also includes a flange 168 engageable with a portion ofbody 116 to connect body 116 to catheter 114.

FIG. 11 is a cross-sectional view of a portion of the catheter assembly110 including a portion of catheter 114 including syringe 118. Luerfitting 128 includes a threaded portion 170 engageable with a threadedportion of a compatible Luer fitting 174 connected to inner shaft 126.Syringe 118 defines an inner shaft receiving lumen 175 sealed withpolymer or rubber seal 176 which can be punctured by a sharpened distalend 167 of inner shaft 126 when threads 172 are advanced into threads170. A fluid connection thus results between the lumen through innershaft 126 and chamber 130. Flange 168 can be part of a seal 171 whichcreates a substantially fluid tight seal between inner shaft 126 andmanifold 164 while allowing inner shaft 126 to move proximally anddistally in the direction as shown by the arrow within manifold 164 ofouter shaft 129. A spring 178 biases inner shaft 126 distally relativeto manifold 164 and outer shaft 129. The travel of inner shaft 126distally is limited by engagement of a stop disc 180 with stop ring 182of manifold 164.

FIG. 12 is a cross-sectional view of a preferred embodiment of catheter114 including inner shaft 126 and outer shaft 129. As shown in FIG. 12,outer shaft 129 is connected by suitable heat adhesive to manifold 164.Outer shaft 129 includes a proximal portion 184 which is preferably aco-braided member having, for example, an inner and outer layer of PEBAand a stainless steel reinforcing braid disposed therebetween. Outershaft 129 also preferably includes a distal portion including a springcoil 188 and an outer polyethylene sheath 186. Connected to the distalend of sheath 186 is hood 163. Hood 163 is preferably formed from anatraumatic material and can include radiopaque material to enhancevisibility by fluoroscopy. Inner tube 126 preferably includes a proximalportion 190 which can be formed from, for example, heat treatedstainless steel and a distal portion 192 which is preferably formed froma Nitinol hypotube. A needle 194 having a distal tip 127 is preferablyattached to the distal portion 192 by a swage collar 196, which may beradiopaque, can engage with hood 163 to limit the distal travel of innershaft 126 relative to outer shaft 129.

It can be appreciated by those skilled in the art that there arenumerous materials which can be advantageously used to construct theapparatus disclosed herein. These materials should be selected in viewof the use to which the apparatus are put.

In use, the needle 194 would be coated with a coating and a first agentat any time prior to the insertion of the catheter into the patient'sbody. Then, once the atraumatic hood 163 was positioned adjacent to thetarget site, the needle, coated with coating that contained the firstagent, would be injected into the target site by pulling the trigger 127and then allowing the needle to remain within the target site until theagent had been properly deployed. If a second agent needed to bedeployed during the procedure the operator would rotate the handle 134to urge the second agent resident in the inner chamber out the sharpeneddistal end of the needle 194 while the needle remained in the targetsite.

Other embodiments than the those described above are also feasible. Forexample, in a sixth embodiment, rather than leaving the injectionstructure within the body of a patient for a predetermined amount oftime, so that the agent may diffuse from the polymer, the polymer andthe agent may, instead, both be left behind in the target site upon theremoval of the injection structure from the target site. In this sixthembodiment the polymer and agent would remain behind to further treatthe targeted site after an initial amount of agent had been dispensedfrom the polymer when the injection structure was first inserted intothe target site.

Similarly, in a seventh embodiment, the coating and the agent may bereleased from the injection structure while the injection structure isresident within the target site. In this seventh embodiment the polymermay be released by virtue of a greater affinity for the target sitetissue, as in a bioadhesive polymer; alternatively, the polymer maysolidify when it comes in contact with the tissue and flake off of theinjection structure as with Atrigel (Atrix) and SABRE (SouthernBiosystems) polymers.

In an eighth embodiment, the agent released from the orifice of theinjection structure may trigger the release of the polymer from theinjection structure instead of merely the entry of the injectionstructure into the body. Moreover, in a ninth embodiment, a sheath maybe placed over the coated injection structure to protect the coating andthe first agent. The sheath may then dissolve after insertion into thetarget site, or it may be removed just prior to the insertion of theinjection structure into the body or the target site.

Furthermore, in a tenth embodiment, as mentioned above, a second agentmay not be needed. In this embodiment, the injection structure would notneed to contain an orifice and the delivery device would not need tocontain a storage reservoir for the second agent. Lastly, in an eleventhembodiment, rather than deploying the second agent after the injectionstructure is inserted into the body, the second agent could be combinedwith the first agent and introduced into the target site with the firstagent through the simple insertion of the injection structure into thetarget site.

In sum, the present invention provides a comprehensive method andapparatus for diagnostic and therapeutic agent delivery. The embodimentsconveyed above are illustrative of the various ways in which the presentinvention may be practiced. Consequently, other embodiments may also beimplemented by those skilled in the art without departing from thespirit and scope of the present invention.

What is claimed is:
 1. A method for injecting an agent into the body ofa patient comprising: (a) providing a catheter having a proximal end anda distal end and a rigid injection structure located at the distal endof the catheter, the rigid injection structure having a piercing tip;(b) covering the rigid injection structure with a coating, the coatingcontaining a first agent, the first agent retained within the coatinguntil the injection structure is urged into a first target site locatedin the body of the patient; (c) urging the piercing tip of the injectionstructure into the first target site; and (d) maintaining the injectionstructure in the first target site for a predetermined amount of time,allowing the agent to release from the injection structure into thebody.
 2. The method of claim 1 further comprising: (e) removing theinjection structure from the first target site; (f) urging the piercingtip of the injection structure into a second target site in the body ofthe patient; and (g) maintaining the injection structure in the secondtarget site for a predetermined amount of time.
 3. The method of claim 1further comprising: (e) injecting a second agent into the first targetsite through a lumen located in the injection structure.
 4. The methodof claim 1 wherein the coating deforms in response to an environmentalstimulus.
 5. The method of claim 1 wherein the first agent is a geneticmaterial.
 6. The method of claim 1 wherein the coating releases thefirst agent in response to an environmental stimulus.
 7. A method forinjecting an agent into the body of a patient comprising: (a) coveringan injection structure having a piercing tip with a coating, the coatingcontaining a first agent; (b) urging the piercing tip of the injectionstructure into a first target site; (c) maintaining the injectionstructure in the first target site for a predetermined time; (d)removing the injection structure from the body of the patient; and (e)treating the coating with the first agent.
 8. The method of claim 7further comprising: (g) positioning the injection structure back intothe first target site.
 9. The method of claim 7 further comprising: (g)urging the piercing tip of the injection structure into a second targetsite in the patient's body.
 10. A method for injecting an agent into thebody of a patient comprising: (a) covering an injection structure havinga piercing tip with a coating, the coating containing a first agent; (b)urging the piercing tip of the injection structure into a first targetsite; (c) maintaining the injection structure in the first target sitefor a predetermined time; wherein the coating is a swellable porouspolymer.
 11. A method for injecting an agent into the body of a patientcomprising: (a) covering an injection structure having a piercing tipwith a coating, the coating containing a first agent; (b) urging thepiercing tip of the injection structure into a first target site; (c)maintaining the injection structure in the first target site for apredetermined time; wherein the coating is charged to attract oppositelycharged therapeutic.
 12. A drug delivery device comprising: a catheterhaving a proximate end and a distal end; an injection structure having apiercing end, the injection structure located at the distal end of thecatheter; and a dispensing chamber located within the catheter, theinjection structure covered with a coating containing an agent, thecoating adapted to release the agent upon entry into the body.
 13. Adrug delivery device comprising: a catheter having a proximate end and adistal end; and an injection structure having a piercing end, theinjection structure located at the distal end of the catheter, theinjection structure covered with a coating containing an agent, thecoating adapted to release the agent upon entry into the body, whereinthe coating is adapted to expand after contact with the tissue of apatient for a predetermined amount of time.